Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China.
J Neuroimmune Pharmacol. 2024 May 8;19(1):17. doi: 10.1007/s11481-024-10117-x.
In our previous study, we concluded that sirtuin 5 (SIRT5) was highly expressed in microglia following ischaemic stroke, which induced excessive neuroinflammation and neuronal injury. Therefore, SIRT5-targeting interventions should reduce neuroinflammation and protect against ischaemic brain injury. Here, we showed that treatment with a specific SIRT5 inhibitor, MC3482, alleviated microglia-induced neuroinflammation and improved long-term neurological function in a mouse model of stroke. The mice were administrated with either vehicle or 2 mg/kg MC3482 daily for 7 days via lateral ventricular injection following the onset of middle cerebral artery occlusion. The outcome was assessed by a panel of tests, including a neurological outcome score, declarative memory, sensorimotor tests, anxiety-like behavior and a series of inflammatory factors. We observed a significant reduction of infarct size and inflammatory factors, and the improvement of long-term neurological function in the early stages during ischaemic stroke when the mice were treated with MC3482. Mechanistically, the administration of MC3482 suppressed the desuccinylation of annexin-A1, thereby promoting its membrane recruitment and extracellular secretion, which in turn alleviated neuroinflammation during ischaemic stroke. Based on our findings, MC3482 offers promise as an anti-ischaemic stroke treatment that targets directly the disease's underlying factors.
在我们之前的研究中，我们得出结论，沉默信息调节因子 5（SIRT5）在缺血性中风后小胶质细胞中高度表达，这诱导了过度的神经炎症和神经元损伤。因此，靶向 SIRT5 的干预措施应该减少神经炎症并保护缺血性脑损伤。在这里，我们表明，用特异性 SIRT5 抑制剂 MC3482 治疗可减轻小胶质细胞诱导的神经炎症，并改善中风小鼠模型的长期神经功能。在大脑中动脉闭塞后，通过侧脑室注射，每天给予小鼠要么载体，要么 2mg/kg 的 MC3482，持续 7 天。通过一系列测试，包括神经功能评分、陈述性记忆、感觉运动测试、焦虑样行为和一系列炎症因子，来评估结果。我们观察到，当用 MC3482 治疗时，梗塞面积和炎症因子显著减少，并且在缺血性中风的早期阶段，长期神经功能得到改善。从机制上讲，MC3482 的给药抑制了膜联蛋白 A1 的去琥珀酰化，从而促进其膜募集和细胞外分泌，进而减轻了缺血性中风期间的神经炎症。基于我们的发现，MC3482 有望成为一种针对缺血性中风的治疗方法，直接针对疾病的潜在因素。
